The present invention relates to drug delivery and diagnostic sampling and, in particular, it concerns systems and methods for the transport of fluids through a biological barrier and production techniques for such systems.
Various techniques are known for drug delivery. A first set of techniques employ oral delivery in the form of pills or capsules. Many drugs cannot, however, be effectively delivered orally due to degradation in the digestive system, poor absorption and/or elimination by the liver.
A second set of techniques deliver drugs directly across the dermal barrier using a needle such as with standard syringes or catheters. These techniques, however, require administration by one trained in their use, and often cause unnecessary pain and/or local damage to the skin. The withdrawal of body fluids for diagnostic purpose using a conventional needle suffers from the same disadvantages. The use of a conventional needle is also undesirable for long term, continuous drug delivery or body fluid sampling.
An alternative delivery technique employs a transdermal patch, usually relying on diffusion mechanisms. The usefulness of transdermal patches, however, is greatly limited by the inability of larger molecules to penetrate the dermal barrier. Transdermal patches are not usable for diagnostic purposes.
Many attempts have been made to develop alternative devices for active transfer of pharmaceutical materials, or for biological sampling, across the dermal barrier. For example, U.S. Pat. No. 5,250,023 to Lee et al. discloses a drug delivery device which includes a plurality of non-hollow microneedles having a diameter of 50-400 micron which perforate the skin to facilitate transfer of larger molecules through the dermal barrier. The microneedles are disclosed as being made of stainless steel.
More recently, much research has been directed towards the development of microneedles formed on chips or wafers by use of micro-machining techniques. This approach promises the possibility of producing numerous, very small needles which are sufficient to form small perforations in the dermal barrier, thereby overcoming the molecular size limitations of conventional transdermal patches, while being safe for use by unqualified personnel. Examples of such work may be found in PCT Publication No. WO 99/64580 to Georgia Tech Research Corp., as well as in the following scientific publications: xe2x80x9cMicro machined needles for the transdermal delivery of drugsxe2x80x9d, S. H. S. Henry et al. (MEMS 98, Heildelberg, Germany, January 1998); xe2x80x9cThree dimensional hollow micro needle and microtube arraysxe2x80x9d, D. V. McAllister et al. (Transducer 99, Sendai, Japan, June 1999); xe2x80x9cAn array of hollow micro-capillaries for the controlled injection of genetic materials into animal/plant cellsxe2x80x9d, K. Chun et al. (MEMS 99, Orlando, Fla., January 1999); and xe2x80x9cInjection of DNA into plant and animal tissues with micromechanical piercing structuresxe2x80x9d, W. Trimmer et al. (IEEE workshop on MEMS, Amsterdam, January 1995). The more recent of these references, namely, the Georgia Tech application and the Chun et al. reference, disclose the use of hollow microneedles to provide a flow path for fluid flow through the skin barrier.
While hollow microneedles are potentially an effective structure for delivering fluids across the dermal barrier, the structures proposed to-date suffer from a number of drawbacks. Most notably, the proposed structures employ microneedles with flat hollow tips which tend to punch a round hole through the layers of skin. The punched material tends to form a plug which at least partially obstructs the flow path through the microneedle. This phenomenon is clearly visible in the scanning electron microscope (SEM) image identified as FIG. 11 of the Chun et al. reference and reproduced here as FIG. 1. This is particularly problematic where withdrawal of fluids is required since the suction further exacerbates the plugging of the hollow tube within the microneedle. The flat ended form of the needles also presents a relatively large resistance to penetration of the skin, reducing the effectiveness of the structure.
A further group of proposed devices employ microneedles formed by in-plane production techniques. Examples of such devices are described in U.S. Pat. No. 5,591,139 to Lin et al., U.S. Pat. No. 5,801,057 to Smart et al., and U.S. Pat. No. 5,928,207 to Pisano et al. The use of in-plane production techniques opens up additional possibilities with regard to the microneedle tip configuration. This, however, is at the cost of very limited density of microneedles (either a single microneedle or at most, a single row of needles), leading to corresponding severe fluid flow rate limitations. The very long proposed needle (about 3 mm) of Smart et al. suffers from an additional very high risk of needle breakage.
A further shortcoming of microneedle structures made by micromachining techniques is the brittleness of the resulting microneedles. Microneedles made from silicon or silicon dioxide are highly brittle. As a result, a significant proportion of the microneedles may fracture due to the stresses occurring during penetration, leaving fragments of the material within the tissue. Furthermore, oblique insertion by an unskilled person could lead to fracture of a very large proportion of the needles, resulting in malfunction of the device.
There is therefore a need for devices and methods based on micro-machining technology for the transport of fluids through the dermal barrier which would reduce or eliminate the problems of blockage by the layers of skin. I would also be highly advantageous to provide devices of this type with highly flexible microneedles to avoid leaving fragments of the microneedles within the skin tissue. Finally, there is a need for practical devices and corresponding systems for implementing diagnosis and treatment of various conditions based on such technology.
The present invention provides devices and methods for the transport of fluids through a biological barrier and production techniques for such devices.
According to the teachings of the present invention there is provided, a device for the transport of fluids through a biological barrier, the device comprising: (a) a substrate defining a substantially planar front face of the device; (b) a plurality of microneedles projecting from the substantially planar front face, each of the microneedles having a maximum width dimension measured parallel to the front face of no more than about 400 xcexcm and a maximum height dimension measured perpendicular to the front face of no more than about 2 mm; and (c) a conduit associated with each of the microneedles and extending through at least part of the substrate, each of the conduits being configured to provide a fluid flow path for transport of fluid through a hole in the biological barrier formed by the corresponding microneedle, wherein each of the microneedles is configured to provide a penetrating tip, the conduit terminating at an opening proximal with respect to the non-hollow penetrating tip.
According to a further feature of the present invention, each of the microneedles is formed as a conical pyramid having a first conical angle and terminating at an apex, and wherein the conduit is formed as a bore intersecting the conical pyramid not at the apex.
According to a further feature of the present invention, each of the microneedles is formed as a hollow tube terminating in a beveled end, a distal extreme of the beveled end serving as the penetrating tip.
According to a further feature of the present invention, the hollow tube has a substantially conical external shape. According to an alternative feature of the present invention, the hollow tube has a substantially cylindrical external shape.
According to a further feature of the present invention, at least an outer surface of the microneedles is formed from metallic material.
According to a further feature of the present invention, at least an outer surface of the microneedles is formed from a super-elastic alloy.
According to a further feature of the present invention, each of the microneedles has a maximum height dimension of no more than about 200 xcexcm.
According to a further feature of the present invention, the plurality of microneedles is implemented as a two-dimensional array including at least 20 microneedles.
There is also provided according to the teachings of the present invention, a method for producing a device for the transport of fluids through a biological barrier, the method comprising: (a) providing a substrate having first and second parallel outward-facing surfaces; (b) processing the substrate so as to form a plurality of bores extending into the substrate from the first surface, each of the bores being substantially symmetrical about a central bore-axis; and (c) processing the substrate so as to remove at least part of the second surface in such a manner is to leave a plurality of conical projections projecting from a remaining thickness of the substrate, each of the conical projections being substantially symmetrical about a central cone-axis, wherein the bores and the conical projections are configured such that each of the bores intersects an external surface of a corresponding one of the conical projections, the bore-axis and the cone-axis being non-coincident.
According to a further feature of the present invention, each of the conical projections terminates at an apex, each of the bores being configured to intersect the corresponding conical projection without removing the apex.
According to a further feature of the present invention, a layer of metallic material is deposited over at least the conical projections.
According to a further feature of the present invention, a layer of a super-elastic alloy is deposited over at least the conical projections.
According to a further feature of the present invention, material of the substrate is removed from within the layer of super-elastic alloy so as to leave conical projections formed substantially exclusively from the layer of a super-elastic alloy.
There is also provided according to the teachings of the present invention, a method for producing a device for the transport of fluids through a biological barrier, the method comprising: (a) providing a substrate; (b) processing the substrate so as to form a plurality of hollow microneedles projecting from a remaining thickness of the substrate, each of the hollow microneedles being substantially symmetrical about a central needle-axis; and (c) eroding part of the hollow microneedles in a manner asymmetric with respect to the needle-axis so as to form beveled-ended hollow microneedles.
According to a further feature of the present invention, the eroding is performed by ion milling.
According to a further feature of the present invention, the eroding is performed by sand blasting.
According to a further feature of the present invention, a layer of metallic material is deposited over at least the beveled-ended hollow microneedles.
According to a further feature of the present invention, a layer of a super-elastic alloy is deposited over at least the beveled-ended hollow microneedles.
According to a further feature of the present invention, material of the substrate is removed from within the layer of super-elastic alloy so as to leave beveled-ended hollow microneedles formed substantially exclusively from the layer of a super-elastic alloy.